The present invention relates generally to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states. It is well known that tumors may express unique proteins associated with their malignant phenotype or may over-express normal constituent proteins in greater number than normal cells. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose and characterize disease by probing the phenotypic identity and biochemical composition and activity of the tumor. Radioactive molecules that selectively bind to specific tumor cell surface proteins provide an attractive route for imaging and treating tumors under non-invasive conditions. In particular, the present inventors have found that radiolabeled ligands to the PSMA protein, often over expressed on prostate cancer cells and the vasculature of other types of solid tumors provide an attractive route for non-invasive imaging and selective targeting of cancer cells.
At least 1 million men suffer from prostate cancer and it's estimated that the disease will strike one in six U.S. men between the ages of 60 and 80. There are more than 300,000 new cases of prostate cancer diagnosed each year. Prostate cancer will affect one in six men in the United States, and the mortality from the disease is second only to lung cancer. An estimated $2 billion is currently spent worldwide on surgical, radiation, drug therapy and minimally invasive treatments, $1 billion of the spending in the U.S. There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer. New agents that will enable rapid visualization of prostate cancer and specific targeting to allow radiotherapy present are needed.
PSMA, also known as folate hydrolase I or glutamate carboxypeptidase II is a transmembrane, 750 amino acid type II glycoprotein which is primarily expressed in normal human prostate epithelium, and is upregulated in prostate cancer, including metastatic disease (4-6). It has been reported that over expression of PSMA in primary prostate cancer correlates with other adverse traditional prognostic factors and independently predicts disease outcome (7). Since PSMA is expressed by virtually all prostate cancers and its expression is further increased in poorly differentiated, metastatic and hormone-refractory carcinomas (8-10), it is a very attractive target for developing radiopharmaceuticals for the diagnosis, staging and treatment of the disease.
PSMA is highly homologous to N-acetylated α-linked acidic dipeptidase (NAALADase), a neuropeptidase which produces the neurotransmitter glutamate and N-acetylaspartate through the hydrolysis of N-acetylaspartylglutamate. Analysis of the crystal structure of PSMA has aided in the understanding of the critical interactions of potent inhibitors within the active site of the enzyme and has led to the design and synthesis of several classes of NAALADase inhibitors that are substrate or transition state analogs.
Radiolabeled anti-PSMA monoclonal antibodies, like Prostascint which is approved by the FDA for diagnostic imaging, and J591 which is in clinical trials for targeted radiotherapy of metastatic prostate cancer (11, 12), have validated PSMA as molecular target for prostate cancer. However, while monoclonal antibodies offer potential for tumor targeting, long circulating half-life and poor tumor penetrability, particularly for bone metastases, limit their effectiveness as diagnostic and therapeutic radiopharmaceuticals (13). For these reasons, there have been only limited clinical successes to date with radiolabeled antibodies, mostly in the treatment of blood-borne cancers such as non-Hodgkin's lymphoma (14).
Small molecules offer significant advantages over antibodies for targeting solid tumors (15). They can be designed with affinities similar to that of monoclonal antibodies. Small molecules exhibit enhanced diffusibility to the extravascular space, and faster blood clearance than antibodies, thus resulting in lower background signal. However, studies carried out by the present inventors as well as others have shown that radiolabeled small molecule PSMA inhibitors exhibit high uptake in the kidneys which has a high expression of the PSMA protein. Accordingly, the kidneys may function to limit a therapeutically effective dose of the radiopharmaceutical from reaching the target tissue.
The present invention overcomes the stated drawback of small molecule PSMA inhibitors by providing the synthesis of a series of dendrimer conjugates of the inventive PSMA inhibitors. Also described are the synthesis of tetramers of the inventive PSMA compounds as well as pharmaceutical compositions of the inventive dendrimers and methods for using the inventive compositions to treat, diagnose and image prostate cancer tissue.